CN1025612C - Acetylenes disubstituted with a heteroaromatic group and a tetralin group having retinoid like activity - Google Patents

Acetylenes disubstituted with a heteroaromatic group and a tetralin group having retinoid like activity Download PDF

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CN1025612C
CN1025612C CN88101234A CN88101234A CN1025612C CN 1025612 C CN1025612 C CN 1025612C CN 88101234 A CN88101234 A CN 88101234A CN 88101234 A CN88101234 A CN 88101234A CN 1025612 C CN1025612 C CN 1025612C
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ethynyl
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tetramethyl
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洛山发·A·S·陈德拉勒拿
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    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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Abstract

Retinoid-like activity is exhibited by compounds of the formula, where R is hydrogen or lower alkyl; A is pyridyl, thienyl, furyl, pyridazinyl, pyrimidinyl or pyrazinyl; n is 0-5; and B is H, -COOH or an ester or amide thereof, -CH2OH or an ester or ester derivative thereof, or -CHO or an acetal derivative thereof, or -COR1 or a ketal derivative thereof where R1 is -(CH2)mCH3 where m is 0 to 4; or a pharmaceutically acceptable salt thereof.

Description

Acetylenes disubstituted with a heteroaromatic group and a tetralin group having retinoid like activity
The present invention relates to have the new compound of retinoid like activity, relate in particular to compound with the acid of ethynyl heteroaromatic and two parts of tetraline group.Acid functional group also can be converted into alcohol, aldehydes or ketones or their derivative, maybe can be alkyl or H.
Can be used for suppressing the general formula 4-(2-(4 of cartilage degradation, 4-dimethyl-6-X)-2-methyl ethylene) open in No. 0133795, the european patent application delivered on January 9th, 1985 of the carboxylic acid derivative of phenylformic acid (wherein: X is tetrahydric quinoline group, chromanyl or thiochroman base), also can consult european patent application 176034A number that delivered on April 2nd, 1986, wherein disclose tetralin compounds with acetylenylbenzene formic acid group.
The present invention includes formula I compound or its pharmaceutically acceptable salt
In the formula, R is hydrogen or low alkyl group; A is pyridyl, thienyl, furyl, pyridazinyl, pyrimidyl or pyrazinyl; N is 0～5; B be H ,-COOH or its pharmaceutically acceptable salt or its ester or acid amides ,-CH 2The derivative of OH or its ether or ester or-CHO or its acetal derivant or-COR, or its ketal derivatives, wherein R 1Be-(CH 2) mCH 3, m is 0～4.
Secondly, the present invention relates to formula I compound is applied to treat tetter such as acne, follicular keratosis, psoriasis, sauriasis, eczema, atopic dermatitis and epithelial cancer.This compounds also can be applicable to treatment of arthritis and other dysimmunities (for example lupus erythematosus), promotes the wound sore to close, treatment sears optical syndromes, and recover the damage that sunlight causes skin.
The invention still further relates to formula I compound and pharmaceutically acceptable vehicle, particularly tool vehicle phase blended formula of medicine in the effect of treatment psoriasis.
At last, the present invention relates to the method for preparation, be included in and have Pd(PQ 3) 4With formula II compound and the reaction of formula III compound, obtain formula I corresponding compounds under (wherein Q is a phenyl) or the similar mixture
Figure 881012343_IMG3
X-A-（CH 2） n-B 1
Ⅱ Ⅲ
In the formula, X is a halogen, is good with I especially, and the definition of n and A is the same; B 1Be H, protected acid, alcohol, aldehydes or ketones; Or
Protected acid, alcohol, aldehydes or ketones are gone protection; Or
Ester is converted into acid or salt; Or
The acid of formula I is converted into salt, or
The acid of formula I is converted into ester; Or
The acid of formula I is converted into acid amides; Or
The acid of formula I is reduced to alcohol or aldehyde; Or
The alcohol of formula I is converted into ether or ester; Or
The alcohol of formula I is oxidized to aldehyde; Or
The aldehyde of formula I is converted into acetal; Or
The ketone of formula I is converted into ketal; Or
The alcohol of formula I is converted into methyl.
General embodiment
" ester " used herein speech relates to and includes the interior any compound of implication of last used this speech of chemical machine classification.Wherein B be-during COOH, then this speech also comprises with alcohol and handles all products that this functional group obtains, for example C 1～C 6Alkyl ester or C 1～C 6The alkane phenylester.At ester be-CH by B 2When the compound deriving of OH obtained, this ester comprised formula-CH 2The compound of OOCR ', wherein R 1Be any replacement or unsubstituted aliphatic group, aromatic group or fat aromatic group, refer to 7～10 carbon atom persons especially.
Preferable ester is to derive by the radical of saturated aliphatic alcohol of 10 or 10 following carbon atoms or aliphatic acid or by the cyclic alcohol of 5～10 carbon atoms or naphthenic acid or saturated aliphatic cyclic alcohol or naphthenic acid to obtain.Best aliphatic ester then is to be derived by low alkyl acid and alcohol to obtain.Here said low alkyl group means the low alkyl group with 1～6 carbon atom.Phenyl ester or low alkyl group phenyl ester also belong to preferable ester.
Acid amides means organic chemistry and classifies the above, for example comprises: sunsubstituting formyl amine and all aliphatic series and aromatics list replace and two substituted amide.Preferable acid amides is to replace and disubstituted acid amides by the radical of saturated aliphatic base of 10 or 10 following carbon atoms or by the cyclic group of 5～10 carbon atoms or radical of saturated aliphatic cyclic group obtain single that derive.Best acid amides is the acid amides that is obtained by low-alkylamine.The single replacement or the two substituted amide that are obtained by aniline or low alkyl group aniline derivatives also belong to preferable acid amides.Sunsubstituting formyl amine also belongs to preferable acid amides.
Acetal and ketal comprise that formula-CK(K is (OR 1) 2, R 1Be low alkyl group) group.K also can be-OR 1O-, R 1Be the straight chain of 2～5 carbon atoms or the low-grade alkylidene of side chain.
Have the functionality that can form pharmaceutically acceptable salt and all can be prepared into this salt for any The compounds of this invention of acid functionality or amine functionality; Pharmaceutically acceptable salt can be any salt, as long as this salt has the parent compound activity, and to using this salt and in this scope, using the patient of this salt can not bring deleterious effect or ill effect.
This salt can be obtained by the acid or the alkali of any organic or inorganic.This salt can be monovalent ion or polyvalent ion.Making us interested especially is and the relevant mineral ions such as sodium, potassium, calcium and magnesium of sour official's energy.Organic amine salt can be used amine, and outstanding available ammonium salt is produced as an alkylamine, dialkylamine and trialkylamine or thanomin.The also available trimethyl-xanthine of salt, Trimethylamine and similar molecular structure are produced.When nitrogen can be enough to generate acid salt, then available any mineral acid or organic acid or alkylating agent such as methyl-iodide were produced this salt.Best acid salt is to produce with mineral acid, as using hydrochloric acid, sulfuric acid or phosphoric acid.Contain the many simple organic acid of 1,2 or 3 carboxyl, all can produce acid salt.
The preferable compound of the present invention be acetylene group and B group respectively with pyridine ring on 2 and 5 (in the nicotinic acid nomenclature 6 and 3, be equivalent to 2/5 in pyridine nomenclature name) or respectively with thienyl or furyl on 5 those compounds that are connected with 2, wherein n is 0,1 or 2; B is-COOH, an alkali metal salt or organic amine salt or its lower alkyl ester or-CH 2OH, and lower alkyl ester.Better compound then is:
6-[2-(5,5,8,8-tetramethyl--5,6,7,8-naphthane-2-yl) ethynyl] Nikithan;
6-[2-(3,5,5,8,8-pentamethyl--5,6,7,8-naphthane-2-yl) ethynyl] Nikithan;
6-[2-(5,5,8,8-tetramethyl--5,6,7,8-naphthane-2-yl) ethynyl] nicotinic acid; With
6-[2-(3,5,5,8,8-pentamethyl--5,6,7,8-naphthane-2-yl) ethynyl] nicotinic acid.
The compounds of this invention can general be offerd medicine or topical administration, decides according to patient's the state of an illness, needs, dosage and the conditions of similarity of privileged site treatment.
Treatment is during tetter, although in some cases, but as treat also oral medication of serious capsule seat sore, usually with local application for well.
The prescription of any local application all can be mixed with solution, suspension, gel, ointment or ointment etc.The prescription of preparing this class local application all had introduction in existing formula of medicine field, for example the 17th edition Remington ' s Pharmaceutical Science one book of continent, Pennsylvania Yi Sitong mark publishing company publication.These compounds also can be mixed with pulvis, sprays, aerosol especially, local dispenser.
In the prescription of this local application, can add other drug,, for example treat xerosis cutis, the protection to irradiate light is provided as secondary objective; Other drug also can be used for treating tetter, protecting from infection, and reduces stimulation, inflammation etc.
If the general medication can be mixed with pulvis, pill, tablet etc., or be mixed with syrup or ingredients is used for oral.Be used for vein or peritoneal administration, then The compounds of this invention can be mixed with the solution or the suspension of energy drug administration by injection.In some cases, also these compounds can be mixed with suppository or sustained release dosage, be used to be deposited on skin facies inferior hepatis or intramuscular injection.
Have any finger disease of the known of susceptibility or the tetter of having found or other for compounds for treating, use the dosage of one or more The compounds of this invention, all can obtain curative effect with similar vitamin A acid.Treatment concentration means can alleviate specific symptoms or postpone it and develops needed drug level.In some cases, this medicine also might be used as prophylactic agent, to prevent the morbidity of a certain specific symptoms.Given treatment concentration will change along with different illnesss, also can be changed according to the severity of patient's symptom with to the susceptibility for the treatment of in some cases.In addition, given treatment concentration can be made optimal selection whenever and wherever possible by the test method of routine.But, can expect that when for example treating acne or other this class tetter, every milliliter of part that contains 0.01～0.5 milligram of preparation can reach curative effect concentration with the system system.If the general medication, the dosage in then 0.01～1 milligram/kg body weight/sky under the thumping majority situation, can obtain prevention effect.
The similar vitamin A acid activity that these compounds had is by the active classical measuring method of vitamin A acid, comprises that vitamin A acid obtains certainly the mensuration of ornithine decarboxylase effect.About vitamin A acid and the original research that reduces dependency between the hyperplasia by Verma ﹠amp; Boutwell finishes (Cancer Research, 1977,37,2196～2201).The document has been introduced ornithine decarboxylase (ODC) activity can increase the biosynthetic condition of polyamines.Confirmed already in other documents that the polyamines synthetic increased relevant or relevant with hyperplasia.Therefore, if the ODC activity can be suppressed, then hyperplasia too much just can be adjusted.Although active all reasons that increase of ODC are unknown so far, know that 12-0-myristoyl phorbol-13-acetic ester (TPA) can be induced the ODC activity.Vitamin A acid then can suppress TPA to active this inducing of ODC.Basically pressing the mensuration that method is carried out described in Cancer Res.:1662～1670,1975 proves, The compounds of this invention also can suppress TPA inducing ODC.
Specific embodiments
The compounds of this invention can be produced by many different chemosynthesis approach.For the present invention is described, this paper has provided a series of synthesis steps, and these steps proved already, synthesized by this step on actual and intension, then can obtain the compound of formula I.Synthetic chemistry man will be readily appreciated that the given condition of this paper is some specific embodiments, but the represented any compound of summary-type I thus.
R base on the phenyl ring follows these steps to preparation for the formula I compound of hydrogen:
The reaction formula I:
Figure 881012343_IMG4
In the formula, n is 0～5, and B is H or protected acid, alcohol, aldehydes or ketones; X is Br, Cl or I, but n is 0 o'clock, is good with Br or I; N is 1～5 o'clock, is good with I then.
R is that the formula I compound of methyl prepares by the reaction formula II.
The reaction formula II:
Figure 881012343_IMG5
In the formula, R is a low alkyl group, and the definition of n, A, B and X is identical with the reaction formula I.
The method for preparing listed each compound in the above-listed reaction formula is summarized as follows:
Ethynyl tetraline part preparation as follows in the reaction formula I: with 2 of formula I, 5-dihydroxyl-2, the 5-dimethylhexane is converted into its corresponding dichloride by handling dihydroxy compound with hydrogen chloride gas.Reaction is blown into the hydrochloric acid suspension of dihydroxy compound to saturated solution approximately carrying out under the room temperature condition with hydrogen chloride gas.In the hydrogen chloride gas saturation history, solution produces the dichloride precipitation, collects the crystalline deposit thing, and water repeatedly washs, then vacuum-drying.
Compound 3 is that the tetramethyl-tetraline can be by 2, and (Freidel-Crafts conditions) reaction under Fu Laideer-Kerafyrm thatch condition of 5-two chloro-2,5-dimethylhexane compound and benzene is produced.For example with 2,5-two chloro-2,5-dimethylhexane compound dissolution is in the benzene that is cooled to about-10～+ 10 ℃.Add and to be about as much as 2,5-two chloro-2, behind the Aluminum chloride anhydrous more than 50% mole of 5-dimethylhexane compound, about 10～50 ℃ preferably at room temperature, mixture was stirred 1～6 hour, be preferably 3 hours.Then solution being refluxed about about 30 minutes to 2 hours, was good with about 1 hour especially.The solution that generates reclaims product by extracting with its change method such as fractionation after acidifying.
The ketone of formula 4 can exist under the aluminum chloride condition, handles tetraline with Acetyl Chloride 98Min. and produces.Promptly under-10～+ 10 ℃, preparation is suspended in the aluminum chloride suspension of polar aprotic solvent at inert atmosphere and low temperature.Inert atmosphere can be argon gas or nitrogen, is good with the former especially.Reaction is suitable for carrying out in the solvent of methylene dichloride one class.With dropping funnel or analogous instrument tetraline and Acetyl Chloride 98Min. are added aluminum chloride suspension, used amount is benchmark with the tetraline.Approximately with Acetyl Chloride 98Min. more than 5% mole and aluminum chloride more than 10% mole.Reaction is stirred in 0.5～4 hour down at 10～50 ℃ and is carried out, and preferably at room temperature carries out about 2 hours.Water and/or ice extract the reaction solution quenching product and further pass through distillation or other proper method purifying then.
Under low temperature and inert atmosphere, by the ethynyl functional group of diisopropyl amide lithium or similar alkali drawing-in system 5.Be reflected in ether solvent such as dioxane ether or cyclic ethers such as tetrahydrofuran (THF), the pyrans etc. and carry out.
More particularly, producing of diisopropyl amide lithium can be cooled to-70～-50 ℃ then by Diisopropylamine is mixed with anhydrous solvent such as tetrahydrofuran (THF) under inert atmosphere.Again at low temperatures, add the alkylate of equimolar amount, as be dissolved in the n-Butyl Lithium in the suitable solvent, generate diisopropyl amide lithium (LDA) behind the mixing appropriate time.The ketone (more than at least 10% mole) of formula 4 is dissolved in the reaction solvent, and solution is cooled to the temperature of LDA mixture, is added to then in this solution.After of short duration mixing, solution is handled with the dialkyl group phosphoryl chloride, and the about diethylchlorophosphate (C2H5O)2P(O)Cl more than 20% mole of You Yiyong is treated to good.The temperature of reaction soln edges up to room temperature then, is added in another diisopropyl amide lithium solution again, and this solution is at low temperature (for example-78 ℃) and inert atmosphere, preferably under argon gas, produces with anhydrous solvent.Then reaction mixture being risen to room temperature again, stir for a long time, be advisable with 10～20 hours, was good with about 15 hours especially.Solution reclaims product with ordinary method after acidifying.
Formula 6 compounds prepare under the anhydrous and oxygen-free condition.What can be used as solvent is the dry ether kind solvent.As dioxane ether or cyclic ethers.For example furans or pyrans, especially tetrahydrofuran (THF).The solution of formula 5 prepares under inert atmosphere such as argon gas or nitrogen earlier, and adding highly basic then is n-Butyl Lithium (about more than 10% mole).This is reflected under-10～10 ℃ of low temperature and begins, and is good with 0 ℃ especially.Reaction mixture is handled with the about fusion zinc chloride more than 10% mole that is dissolved in reaction solvent after 30 minutes to 2 hours of short duration stirring.This mixture is under about starting temperature, and restir 1～3 hour rose to temperature about room temperature in 10～40 minutes then.
Need with the protected heteroaromatics of formula 6 compound couplings, can produce by its corresponding acid, alcohol, ketone or aldehyde.Acid, alcohol, these raw materials of aldehydes or ketones all can obtain from the chemical plant or available known method is produced.The esterification of the acid acid in the solution that is dissolved in suitable alcohol that can under having thionyl chloride, reflux, or exist under dicyclohexylcarbodiimide and the dimethyl aminopyridine acid and pure the reaction.Alcohol, aldehyde and ketone are protected by be divided into generation ether and ester, acetal or ketal with following currently known methods.
In order to strengthen n value before carrying out coupled reaction, every this compounds that can not be obtained by the commercial channel all can be under Arndt-Esther condition, and continuous treatments B is-heteroaromatics of COOH, make it become homologue.Then these acid are made its esterification by the above conventional processing that provides.
Heteroaromatics is dissolved in the anhydrous response solvent, can produces formula 7 compounds.The consumption of heteroaromatics roughly is equivalent to the volumetric molar concentration of formula 6.Under about-10～+ 10 ℃ temperature, this solution is introduced four-triphenyl phosphine palladium of being suspended in reaction solvent (be equivalent to approximately reagent 5～10% moles) suspension.This mixture is added to the prefabricated solution of formula 6 in this mixture of firm preparation after of short duration stirring about 15 minutes, reinforcedly roughly at room temperature carries out.This solution at room temperature after about 15～25 hours long-time stirring, makes the reaction solution quenching with acid, separates and purified product with ordinary method then, obtains formula 7 compounds.
Preparation n is that another method of 1～5 compound is that to make B with above-mentioned Arndt-Esther method be that sour formula 7 compounds become homologue.
Be easy to produce by acid of formula 7 deutero-and salt from its corresponding acid.Can produce acid with the alkaline saponification that alkali metal base carries out.For example: be preferably under inert atmosphere and the room temperature, the ester of formula 7 can be that potassium hydroxide is dissolved in polar solvent such as the alkanol with about alkali more than 3 moles, then with solution stirring 15～20 hours, and cooling according to a conventional method, acidifying and recycle-water hydrolysis products.
Acid amides can be produced with any suitable amidation method known in the art.A kind of method for preparing this compounds is that acid is converted into chloride of acid, handles this compound with ammonium hydroxide or suitable amine again.For example, at room temperature, handle about 30 minutes of acid with pure alkaline solution such as ethanol potassium hydroxide (about more than 10% mole).Remove solvent, residue is dissolved in organic solvent,, successively handle again with dialkylformamide and the oxalyl chloride more than 10 times as diethyl ether.These processing are all carried out under the cold condition in-10～+ 10 ℃.Last described solution stirred 1～4 hour at low temperatures, was good with 2 hours.Remove solvent, residue is dissolved in inert inorganic solvent such as the benzene, be cooled to about 0 ℃, handle with strong aqua again.The mixture that generates stirred 1～4 hour at low temperatures, reclaimed product according to a conventional method.
Alcohol the available thionyl chloride of preparation or additive method with corresponding acid be converted into chloride of acid (J.March " Advanced Organic Chemistry "; 2ndEdition; McGraw-Hill Book Company); use sodium borohydride reduction chloride of acid (March then; the same; the 1124th page), can obtain corresponding alcohol.In addition, also available at low temperatures lithium aluminum hydride ester reduction.With suitable alkylogen, under the williamson reaction condition,, obtain corresponding ether with the alkylation of this class alcohol (March, the same, the 357th page).
Aldehyde can be by corresponding primary alconol preparation, and its used moderate oxygenant for example has: the dichloromethane solution of two chromic acid pyridines (Corcy, E.J., Schmidt.G., Tet.Lett., 399,1979) or the dichloromethane solution (Omura of methyl-sulphoxide/oxalyl chloride, K., Swern, D.Tetrahedron, 1978,34,1651).
Handle suitable aldehyde with alkyl Grignard reagent or similar reagents, and then use above-mentioned reagent oxidation, then can prepare ketone by aldehyde.
Acetal or ketal can be the same by March(, the 810th page) described method, produce by corresponding aldehydes or ketones.
B is that the compound of H can be by corresponding fontanel for the preparation of heterocycle body, and its halogen is good with I especially.This halogenated heterocyclic compound is pressed the reaction formula I, says that exactly to press embodiment 9 described, reacts with ethynyl chlorination zinc body.B is that the halogen-substituted heterocyclic compound of H can obtain by the commercial channel, or presses the described method preparation of document.In addition, n be 1～5 and B be that the compound of H can be produced by reducing suitable aldehydes or ketones with yellow toot imperial reduction method or similar reaction (March, the same, the 1119th page).
It is the method for the formula I compound of methyl that the reaction formula II has provided preparation R.They are under Fu Laideer-Krafft condition, and with 2,2,5,5-tetramethyl-tetrahydrofuran (THF) (formula 9) and toluene (formula 8) prepare.Furans more than 3～4 moles is added in the toluene that is cooled to about-10～15 ℃, adds the Aluminum chloride anhydrous that is about as much as the toluene mole number to stir in a small amount in batches again.Finish when adding aluminum chloride, remove cooling bath, reaction at room temperature is no more than 20 hours.Then solution being refluxed about 1～3 hour, was good with about 2 hours.After the backflow, adding dilute hydrochloric acid solution, is good with about 3N concentration especially, makes the reaction solution quenching.From water layer abstraction reaction product, be further purified product with proper method such as fractionation.
Other synthesis steps that the compound of reaction formula II are converted into formula I compound can be undertaken by given step and the condition of above-mentioned reaction formula I is discussed.
With following embodiment the present invention is described, but is not to limit its scope.
Embodiment 1
2,5-two chloro-2,5-dimethylhexane
Hydrogen chloride gas is blown into 48 gram (0.33 moles) 2,5-dimethyl-2, the suspension of 5-hexylene glycol in the 600ml concentrated hydrochloric acid is saturated to solution.The crystallized product that filter to collect generates washes with water repeatedly, and vacuum-drying obtains the title compound of white crystalline solid.
PMR（CDCl 3）：δ1.60（12H，s），1.94（4H，s）.
Embodiment 2
1,1,4,4-tetramethyl--1,2,3,4-tetralin
With 100 gram (0.55 moles) 2,5-two chloro-2 after the solution vigorous stirring of 5-dimethylhexane 300ml benzene, place ice bath to cool off, and handle with a small amount of with 45 gram (0.34 mole) Aluminum chloride anhydrouss in batches.This mixture at room temperature stirred 3 hours, refluxed 1 hour, poured into after the cooling in ice and the hydrogen chloride mixture.Reclaim organic layer and extract water layer, merge organic extracting solution, water, saturated Na with ether 2CO 3Solution and saturated NaCl solution washing are through MgSO 4Dry.
Remove desolvate after, (78 ℃, 0.8mm) residue obtains the title compound of colourless liquid in fractionation.
PMR（CDCl 3）：δ1.3（12H，s），1.7（4H，s），7.1（2H，m），7.5（2H，m）.
Embodiment 3
1,1,4,4-tetramethyl--1,2,3,4-tetrahydrochysene-6-acetonaphthone
Under argon atmospher, place cryosel to bathe cooling in the suspension of 15ml methylene dichloride in 3.45 gram (25.9 mmole) aluminum chloride, when stirring, in 0.5 hour, restrain (21.2 mmoles) 1,1,4 with dropping funnel with 4,4-tetramethyl--1,2,3, the mixture of 4-tetraline (being obtained by embodiment 2) and 1.94 gram (24.7 mmole) Acetyl Chloride 98Min.s drips processing.Remove ice bath then, at room temperature mixture was stirred 2 hours, make the reaction solution quenching with ice again.Four receive organic layer, and extract water layer with methylene dichloride 2 * 50ml.
Merge organic extracting solution, water, saturated NaHCO 3Solution washing is through MgSO 4Dry.Vacuum is removed solvent, and residue distills (90 ℃ with bulb (Kugelrohr); 0.45mm), obtain the colorless oil title compound.
PME（CDCl 3）：δ1.32（6H，s），1.33（6H，s），1.72（4H，s），2.60（3H，s），7.41（1H，d，J～8.8Hz），7.71（1H，dd，J～8.8，2.6Hz）7.96（1H，d，J～2.6Hz）
Embodiment 4
1,1,4,4-tetramethyl--6-ethynyl-1,2,3,4-tetralin
Under argon filling and-78 ℃, 1.6M(11.52 mmole with injection tubulose 7.2ml) hexane solution of n-Butyl Lithium is added drop-wise to through 1.1572 of stirring and restrains (11.4359 mmole) Diisopropylamines in the solution of 20ml anhydrous tetrahydro furan, this mixture stirred 1 hour down at-78 ℃, then with 2.635 gram (11.4391 mmoles) 1,1,4,4-tetramethyl--1,2,3,4-tetrahydrochysene-6-acetonaphthone drips processing in the solution of 6ml anhydrous tetrahydro furan.Stirred 1 hour down at-78 ℃, handle this mixture with 1.97 gram (11.4175 mmole) diethyl phosphonyl chlorides.Remove cooling bath, at room temperature stirred this mixture 3.5 hours.Under-78 ℃, with double ended meedle this mixture is transferred to N-Lithiodiisopropylamide (with the 1.6M23.2 mmole of 2.31 gram (22.8322 mmole) Diisopropylamines and 14.5ml) n-Butyl Lithium hexane solution and produces again) in 60 milliliters of anhydrous tetrahydrofuran solutions.At room temperature begin to stir continuous 20 hours.Reaction solution is with the quenching of 50ml water and use the 25ml3N hcl acidifying.Extract the recovery reaction product by 5 * 50ml pentane, merge organic extracting solution, with 3N hydrochloric acid, water, saturated NaHCO 3Solution and saturated NaCl solution washing are through MgSO 4Dry.Remove solvent then, with dodging chromatography (silicon-dioxide, the hexane solution of 5% ethyl acetate) purifying residue, again with bulb distillation (60 ℃ 0.2mm), obtain the colorless oil title compound.
PMR（CDCl 3）：δ1.25（6H，s），1.27（6H，s，），1.66（4H，s），2.98（1H，s，7.24（2H，s），7.46（1H，s）
Embodiment 5
1,1,4,4,6-pentamethyl--1,2,3,4-tetralin
26.6 gram (0.2 mole) Aluminum chloride anhydrouss are added 40 gram (0.4341 mole) toluene and 25 gram (0.195 moles) 2,2,5 to stir in a small amount in batches, in cooling (0 ℃) mixture that 5-tetramethyl-tetrahydrochysene leaf is muttered.Remove cooling bath, mixture at room temperature stirred 20 hours, reflux 2 hours.Reaction mixture is cooled to room temperature, and on the rocks then and 100ml3N hydrochloric acid mixture makes its quenching.Separate organic layer, water layer extracts with 3 * 75ml ether.After organic extracting solution merges, with 3N hydrochloric acid, saturated NaHCO 3Solution and saturated NaCl solution washing are used MgSO again 4Dry.Vacuum is removed solvent, and the fractionation residue obtains the colorless oil title compound.
PME（CDCl 3）：1.30（6H，s），1.32（6H，s，），1.70（4H，s），2.33（3H，s），6.98（1H，d，J～7Hz），7.14（1H，s），7.23（1H，d，J～7Hz）
Handle with similar approach, but replace toluene, can prepare following compounds with suitable alkane phenyl:
1,1,4,4-tetramethyl--6-ethyl-1,2,3,4-tetralin;
1,1,4,4-tetramethyl--6-propyl group-1,2,3,4-tetralin;
1,1,4,4-tetramethyl--6-butyl-1,2,3,4-tetralin;
1,1,4,4-tetramethyl--6-amyl group-1,2,3,4-tetralin;
Embodiment 6
1,1,4,4,7-pentamethyl--6-acetyl-1,2,3,4-tetralin;
13.72 gram (102.9 mmole) aluminum chloride are placed the molten argon filling cooling of acetone ice in 40 milliliters of ethylene dichloride suspension, in one hour, restrain (84.56 mmoles) 1 with 17.11,1,4,4,6-pentamethyl--1,2,3,4-tetraline (taking from embodiment 5) is added to this suspension in the drips of solution of 10 milliliters of ethylene dichloride.Remove cooling fluid, after mixture at room temperature stirs 3 hours, pour in the ice, separate organic layer also with 3 * 75 milliliters of dichloromethane extraction water layers.Merge organic layer, wash with water for several times, use saturated NaHCO again 3Solution and saturated NaCl solution washing are through MgSO 4After the drying, vacuum is removed solvent, residue through the bulb distillation (
PMR（CDCl 3）：δ1.30（6H，s），1.32（6H，s），1.70（4H，s），2.51（3H，s），2.59（3H，s），7.16（1H，s），7.69（1H，s）
In addition, also the compound of embodiment 5 preparations can be converted into corresponding acetyl form.
Embodiment 7
1,1,4,4,7-pentamethyl--6-ethynyl-1,2,3,4-tetralin
Under argon filling and-78 ℃, with 4.9 milliliters of 1.6M(7.84 mmoles) hexane solution of n-Butyl Lithium is added drop-wise to 794.2 milligrams of (7.8486 mmole) Diisopropylamines in the solution of the stirring of 7 milliliters of anhydrous tetrahydro furans.This solution stirred 1.25 hours down at-78 ℃, restrained (7.7749 mmoles) 1,1,4,4 with double ended meedle with 1.9 then, and 7-pentamethyl--6-acetyl-1,2,3,4-tetralin moves in 4 milliliters of anhydrous tetrahydrofuran solutions and handles.Mixture is handled with 1.3134 gram (7.6117 mmole) diethylchlorophosphate (C2H5O)2P(O)Cls after stirring 1 hour under-78 ℃.Remove cooling bath, mixture at room temperature stirred 3 hours.At-78 ℃, with double ended meedle this mixture is transferred to diisopropyl amide lithium (preparation as stated above is with 1.5884 gram (15.6972 mmole) Diisopropylamine and 10 milliliters of 1.6M(16 mmoles) n-Butyl Lithium in hexane) in the solution of 15 milliliters of anhydrous tetrahydro furans.Remove cooling bath, after mixture at room temperature stirs 15 hours,, use the 3N hcl acidifying again to pH1 with 50 ml water quenchings.With 3 * 75 milliliters of Petroleum ether extraction mixtures, merge organic extraction, use saturated NaHCO 3Solution and saturated NaCl solution washing are through MgSO 4Dry.Vacuum is removed solvent, and residue is with dodging chromatography (silicon-dioxide; The hexane solution of 3% ethyl acetate) purifying, (50 ℃, 0.05mm obtains the colorless oil title compound through the bulb distillation again.
PMR（CDCl 3）：δ1.28（12H，s），1.67（4H，s），1.42（3H，s），3.20（1H，s），7.15（1H，s），7.44（1H，s）
Use similar approach, 6 basic analogues of burning of embodiment 6 be converted into the ethynyl derivatives serving of following compounds:
1,1,4,4-tetramethyl--6-ethyl-7-ethynyl-1,2,3,4-tetralin;
1,1,4,4-tetramethyl--6-propyl group-7-ethynyl-1,2,3,4-tetralin;
1,1,4,4-tetramethyl--6-butyl-7-ethynyl-1,2,3,4-tetralin; And
1,1,4,4-tetramethyl--6-amyl group-7-ethynyl-1,2,3,4-tetralin.
Embodiment 8
6-chlorine apellagrin ethyl ester
With 15.75 gram (0.1 mole) 6-chlorine apellagrins, 6.9 gram (0.15 mole) ethanol, 22.7 gram (0.11 mole) dicyclohexylcarbodiimide and 3.7 gram (0.03 mole) dimethyl aminopyridines in the mixture heating up backheat of 200 milliliters of methylene dichloride 2 hours.After the mixture cooling, vacuum is removed solvent, and residue obtains the title compound of low melting point white solid after dodging chromatography.
PMR（CDCl 3）：δ1.44（3H，t，J～6.2Hz）4.44（2H，q，J～6.2Hz），7.44（1H，d，J～8.1Hz），8.27（1H，dd，J～8.1Hz，3Hz），9.02（1H，d，J3Hz）.
But this method esterification is used to prepare the acid that any halogen of following compound replaces:
2-(2-chloropyridine-5-yl) ethyl acetate;
5-(2-chloropyridine-5-yl) Valeric acid ethylester;
2-(2-iodofuran-5-yl) ethyl acetate;
5-(2-iodofuran-5-yl) Valeric acid ethylester;
2-(2-iodothiophen-5-yl) ethyl acetate;
5-(2-iodothiophen-5-yl) Valeric acid ethylester;
2-(3-chlorine pyridazine-6-yl) ethyl acetate; And
5-(3-chlorine pyridazine-6-yl) Valeric acid ethylester.
Embodiment 9
6-[2-(5,5,8,8-tetramethyl--5,6,7,8-naphthane-2-yl) ethynyl] Nikithan
The reaction vessel that will be used for the sheet method is dried under vacuum, and all operation is all carried out under the argon of anaerobic or nitrogen atmosphere.With 1.3 milliliters of 1.6M(2.32 mmoles) hexane solution of n-Butyl Lithium is added drop-wise to 417.6 milligrams of (1.9667 mmoles) 1,1,4 of 0 ℃, 4-tetramethyl--1,2,3,4-tetrahydrochysene-6-ethynyl naphthalene is in the solution of 3 milliliters of anhydrous tetrahydro furans.This mixture stirred 10 minutes down at 0 ℃ earlier, at room temperature stirred 15 minutes again, was cooled to after 0 ℃ by double ended meedle with 290 milligrams of (2.1279 mmole) fusion zinc chloride in the solution-treated of 4 milliliters of anhydrous THF.This mixture stirred 45 minutes down at 0 ℃ earlier, at room temperature stirred 15 minutes again.With double ended meedle 361.1 milligrams of (1.9455 mmole) 6-chlorine apellagrin ethyl esters are transferred to 420 milligrams of fat palladiums of (0.3635 mmole) four-triphen in the suspension of 4 milliliters of anhydrous THF in the solution of 4 milliliters of anhydrous THF, the mixture that generates at room temperature stirred 15 minutes, handled with the alkynyl zinc solution of above-mentioned preparation by double ended meedle then.Reaction mixture at room temperature stirred 70 hours, with ice and the quenching of 30 milliliters of 3N hydrochloric acid.The mixture that generates extracts with 3 * 50 milliliters of ethers, and the combined ether extracting solution is used saturated NaHCO more successively 3Solution and saturated NaCl solution washing are through MgSO 4Dry.Vacuum filtration and concentrated ethereal solution.The raw product that generates is earlier through dodging chromatography (silicon-dioxide; 10% ethyl acetate isohexane solution), use the hexanes mixtures crystallization of ethyl acetate again, obtain shallow milk look solid title compound.
PMR（CDCl 3）：δ1.28（6H，s），1.30（6H，s），1.43（3H，t，J～7.1Hz），1.69（4H，s），4.42（2H，q，J～7.1Hz），7.31（1H，d，J～8.3Hz），7.38（1H，d，J～8.3Hz），7.59（1H，d，J～8.3Hz），7.60（1H，s），8.28（1H，dd，J～8.3Hz，2.5Hz），9.20（1H，d，J～2.5Hz）.
Handle by similar approach, but with 1,1 of embodiment 7,4,4,6-pentamethyl--6-ethynyl-1,2,3,4-tetraline or another compound for preparing by this embodiment replace above-mentioned 1,1,4,4-tetramethyl--compound replaces 6-chlorine apellagrin ethyl ester as the plain heterocycle that replaces of suitable then available suitable fontanel, can prepare following compounds:
6-[2-(3,5,5,8,8-pentamethyl--5,6,7,8-naphthane-2-yl) ethynyl] Nikithan;
6-[2-(3-ethyl-5,5,8,8-tetramethyl--5,6,7,8-naphthane-2-yl) ethynyl] Nikithan;
6-[2-(3-amyl group-5,5,8,8-tetramethyl--5,6,7,8-naphthane-2-yl) ethynyl] Nikithan;
[2-((5,5,8,8-tetramethyl--5,6,7,8-naphthane-2-yl) ethynyl) pyridine-5-yl] ethyl acetate;
3-[2-((5,5,8,8-tetramethyl--5,6,7,8-naphthane-2-yl) ethynyl) pyridine-5-yl] ethyl propionate;
5-[2-((5,5,8,8-tetramethyl--5,6,7,8-naphthane-2-yl) ethynyl) pyridine-5-yl] Valeric acid ethylester;
[5-((5,5,8,8-tetramethyl--5,6,7,8-naphthane-2-yl) ethynyl) furans-2-yl] ethyl acetate;
3-[5-((5,5,8,8-tetramethyl--5,6,7,8-naphthane-2-yl) ethynyl) furans-2-yl] ethyl propionate;
5-[5-((5,5,8,8-tetramethyl--5,6,7,8-naphthane-2-yl) ethynyl) furans-2-yl] Valeric acid ethylester;
[5-((5,5,8,8-tetramethyl--5,6,7,8-naphthane-2-yl) ethynyl) thiophene-2-yl] ethyl acetate;
3-[5-((5,5,8,8-tetramethyl--5,6,7,8-naphthane-2-yl) ethynyl) thiophene-2-yl] ethyl propionate;
5-[5-((5,5,8,8-tetramethyl--5,6,7,8-naphthane-2-yl) ethynyl) thiophene-2-yl] Valeric acid ethylester;
[6-((5,5,8,8-tetramethyl--5,6,7,8-naphthane-2-yl) ethynyl) pyridazine-3-yl] ethyl acetate;
3-[6-((5,5,8,8-tetramethyl--5,6,7,8-naphthane-2-yl) ethynyl) pyridazine-3-yl] ethyl propionate;
5-[6-((5,5,8,8-tetramethyl--5,6,7,8-naphthane-2-yl) ethynyl) pyridazine-3-yl] Valeric acid ethylester;
[5-((5,5,8,8-tetramethyl--5,6,7,8-naphthane-2-yl) ethynyl) pyrimidine-2-base] ethyl acetate;
3-[5-((5,5,8,8-tetramethyl--5,6,7,8-naphthane-2-yl) ethynyl) pyrimidine-2-base] ethyl propionate;
5-[5-((5,5,8,8-tetramethyl--5,6,7,8-naphthane-2-yl) ethynyl) pyrimidine-2-base] Valeric acid ethylester;
[2-((5,5,8,8-tetramethyl--5,6,7,8-naphthane-2-yl) ethynyl) pyrimidine-5-yl] ethyl acetate;
3-[2-((5,5,8,8-tetramethyl--5,6,7,8-naphthane-2-yl) ethynyl) pyrimidine-5-yl] ethyl propionate;
5-[2-((5,5,8,8-tetramethyl--5,6,7,8-naphthane-2-yl) ethynyl) pyrimidine-5-yl] Valeric acid ethylester;
[5-((5,5,8,8-tetramethyl--5,6,7,8-naphthane-2-yl) ethynyl) pyrazine-2-yl] ethyl acetate;
3-[5-((5,5,8,8-tetramethyl--5,6,7,8-naphthane-2-yl) ethynyl) pyrazine-2-yl] ethyl propionate; And
5-[5-((5,5,8,8-tetramethyl--5,6,7,8-naphthane-2-yl) ethynyl) pyrazine-2-yl] Valeric acid ethylester.
Embodiment 10
6-[2-(5,5,8,8-tetramethyl--5,6,7,8-naphthane-2-yl) ethynyl] nicotinic acid is the dehydrated alcohol vacuum outgas, feeds nitrogen simultaneously.With 800 milliliters of 1.65M(1.32 mmoles) ethanol of potassium hydroxide and the aqueous solution handles 188 milligrams of (0.521 mmole) 6-[2-(5,5,8,8-tetramethyl--5,6,7,8-naphthane-2-yl) ethynyl] Nikithan is in the solution of 2 milliliters of dehydrated alcohols.After mixture at room temperature stirred 18 hours, vacuum was removed solvent.Residue is dissolved in water also extracts with 50 milliliters of ethers, behind the eliminating ether, water layer uses the Glacial acetic acid acidifying also with 4 * 50 milliliters of ethers extractions.The combined ether extracting solution, water, saturated NaCl solution washing are through MgSO 4Dry.Vacuum is removed solvent, obtains the title compound of light yellow solid.
PMR（CDCl 3）：δ1.31（12H，s），1.71（4H，s），17.34（1H，d，J～7.8Hz），7.40（1H，d，J～7.8Hz），7.62（1H，s），8.39（1H，dd，J～7.3Hz，2.1Hz），9.33（1H，d，J～2.1Hz）.
By same procedure, any ester of embodiment 9 preparations all can be converted into its acid accordingly, refers to 6-[2-(3 especially, and 5,5,8,8-pentamethyl--5,6,7,8-naphthane-2-yl) ethynyl] nicotinic acid.
Embodiment 11
2-[2-((5,5,8,8-tetramethyl--5,6,7,8-naphthane-2-yl) ethynyl]-the 5-4-hydroxymethylpiperidine
250 milliliter of 3 neck flask, dropping funnel, nitrogen inlet tube and thermometer of agitator are housed.379.5 milligrams of (10 mmole) lithium aluminum hydrides are housed in 30 milliliters of anhydrous diethyl ether solutions in the flask.Fill under the nitrogen, solution be cooled to-65 ℃,, drip 3.6148 gram (10 mmole) 6-[2-(5,5,8,8-tetramethyl--5,6,7,8-naphthane-2-yl so that temperature is no more than-60 ℃ speed) ethynyl] Nikithan is in 15 milliliters of dry ether solution.Mixture stirred 1 hour down at-30 ℃, added 300 milligrams of (3.4 mmole) ethyl acetate then to destroy superfluous hydride.Add 3 milliliters of these reaction mixtures of saturated ammonium chloride solution hydrolysis, make temperature rise to room temperature simultaneously.Mixture after filtering, residue washs with ether.The ether layer is again with the saturated nacl aqueous solution washing, through MgSO 4After the drying, vacuum concentration.The chromatography purification residue carries out crystallization then, obtains title compound.
Embodiment 12
2-[2-(5,5,8,8-tetramethyl--5,6,7,8-naphthane-2-yl) ethynyl]-5-acetyl-o-methyl pyridine
At room temperature, with 3.195 gram (10 mmole) 2-[2-(5,5,8,8-tetramethyl--5,6,7,8-naphthane-2-yl) ethynyl]-5-4-hydroxymethylpiperidine, 600 milligrams of (10 mmole) Glacial acetic acid, 2.06 gram (10 mmole) dicyclohexylcarbodiimide and 460 milligrams of (3.765 mmole) 4-dimethylaminopyridines be in the solution stirring of 150 milliliters of methylene dichloride 48 hours.Filter reaction mixture, residue is with 50 milliliters of washed with dichloromethane.Vacuum concentrated filtrate, residue are behind chromatography purification, and crystallization obtains title compound.
By same procedure, any acid of the present invention or ester all can be converted into its corresponding primary alconol analogue.
Embodiment 13
2-[2-(5,5,8,8-tetramethyl--5,6,7,8-naphthane-2-yl) ethynyl]-pyridine-5-formaldehyde
Four neck flasks, thermometer, 2 all pressures funnels that have drying tube that agitator is housed are equipped with the new distillatory oxalyl chloride of 1.396 grams (11 mmole) in 25 milliliters of dichloromethane solutions in the flask.Solution is cooled to-60 ℃, drips in 5 milliliters of dichloromethane solutions and handles with 1.875 gram (24 mmole) methyl-sulphoxides (being obtained by the hydrolith distillation) in 5 minutes then.Reaction mixture stirred 10 minutes down at-60 ℃.Again in 5 minutes, with 3.195 gram (10 mmole) 2-[2-(5,5,8,8-tetramethyl--5,6,7,8-naphthane-2-yl) ethynyl]-the 5-4-hydroxymethylpiperidine is added in this reaction mixture in 10 milliliters of dichloromethane solutions.Mixture restir 15 minutes is handled with 5.06 gram (50 mmole) triethylamines then.Remove cooling bath, make the temperature of mixture rise to room temperature.30 ml waters are added to this mixture, and continuously stirring is 10 minutes again.Separate organic layer also with 20 milliliters of dichloromethane extraction water layers.Merge organic layer, use rare HCl, water and rare Na successively 2Na 2CO 3Solution washing, MgSO 4Dry.Vacuum filtration and concentrated solution, residue obtains title compound through the chromatography purification post crystallization.
The all available this method of alcohol of the present invention are oxidized to its corresponding aldehyde.
Embodiment 14
2-[2-(5,5,8,8-tetramethyl--5,6,7,8-naphthane-2-yl) ethynyl]-the 5-(1-hydroxypropyl) pyridine
3 neck flask that mechanical stirrer is housed, by the reflux condensing tube of drying tube protection with by all pressures dropping funnel of drying tube protection; 4 milliliters of 3M(12 mmoles are housed in the flask) ethereal solution of ethyl-magnesium-bromide; in in ice is molten, cooling off; along with vigorous stirring slowly adds 3.174 gram (10 mmole) 2-[2-(5,5,8; 8-tetramethyl--5; 6,7,8-naphthane-2-yl) ethynyl] pyridine-5-formaldehyde is in 10 milliliters of dry ether solution.Remove cooling bath, mixture heating up refluxed 3 hours, added 5 milliliters of saturated ammonium chloride solutions again behind the cooling mixture in cryosel is bathed.Mixture restir 1 hour filters then, and residue washs 2 times with ether, and each 10 milliliters, ethereal solution is used MgSO after separating 4Drying, vacuum is removed ether.Residue is behind chromatography purification, and crystallization obtains title compound.
By same procedure, but replace above-mentioned pyridine compounds with other any heteroaromatic aldehyde of the present invention that can be converted into secondary alcohol.
This class secondary alcohol can be converted into its corresponding ketone, and method adopts embodiment 13 described, promptly with its with identical reagent, press the roughly the same amount of reagent of reactant use, and substantially the same condition.
Embodiment 15
2-[2-(5,5,8,8-tetramethyl--5,6,7,8-naphthane-2-yl) ethynyl]-5-dimethoxy-methyl pyridine
One is equipped with the Dean and Stark apparatus round-bottomed flask, and this device is configured in below the reflux condensing tube of drying tube protection.3.174 gram (12 mmole) 2-[2-(5 are housed in the bottle, 5,8,8-tetramethyl--5,6,7,8-naphthane-2-yl) ethynyl] mixture of pyridine-5-formaldehyde, 4.80 milligrams of (15 mmole) anhydrous methanols, 2 milligrams of tosic acid-hydrates and 10 milliliters of dry-out benzene, fill reflux under the nitrogen, the moisture in being collected in dean stark trap is near theoretical value.To react mixing and be cooled to room temperature, use 5 milliliter of 10% sodium hydroxide solution and water (2 times, each 5 milliliters) washing successively, use MgSO then 4Drying, filtering solution, vacuum is removed solvent, and residue is behind chromatography purification, and crystallization obtains title compound.
Use similar approach, any aldehydes or ketones of any compound of the present invention all can be converted into acetal or ketal.
Embodiment 16
These compounds are mixed with various prescriptions, are used for topical, effect is rather good.Its prescription is as follows:
Composition weight (%) composition weight (%)
Solution gel
Retinoids 0.1 retinoids 0.1
BHT 0.1 BHT 0.1
Alcohol (American Pharmacopeia) 58.0 alcohol (American Pharmacopeia) 97.8
Poly(oxyethylene glycol) 400 NF 41.8 hydroxypropylcelluloses 2.0

Claims (9)

1, the method for preparation has been included in Pd (PQ 3) 4(Q is a phenyl) exists down, and formula II compound and the reaction of formula III compound generate corresponding formula I compound, and need, and protected acid, alcohol or aldehyde are gone protection,
Figure 881012343_IMG1
In the formula, R is hydrogen or low alkyl group;
A is pyridyl, thienyl, furyl, pyridazinyl, pyrimidyl or pyrazinyl;
N is 0～5;
B is-COOH or its pharmaceutically acceptable salt or its ester ,-CH 2The derivative of OH or its ether or ester or-CHO or its acetal derivant;
B 1Be H, protected acid, alcohol or aldehyde;
X is a halogen.
2, according to the process of claim 1 wherein that R is hydrogen or methyl, n is 0,1 or 2, and A is a pyridyl.
3, according to the method for claim 2, B wherein 1Be protected acid.
4, according to the method for claim 3, wherein the compound of Sheng Chenging is 6-[2-(5,5,8, and 8-tetramethyl--5,6,7,8-naphthane-2-yl) ethynyl] Nikithan or 6-[2-(3,5,5,8,8-pentamethyl--5,6,7,8-naphthane-2-yl) ethynyl] Nikithan.
5, according to the process of claim 1 wherein that A is a thienyl, B 1Be protected acid.
6, according to the process of claim 1 wherein that A is a furyl, B 1Be protected acid.
7, according to the process of claim 1 wherein that A is pyridazinyl, pyrimidyl or pyrazinyl, B 1Be protected acid.
8, according to the process of claim 1 wherein that X is I.
9, according to the method for claim 1, obtain 6-[2-(5,5,8,8-tetramethyl--5,6,7,8-naphthane-2-yl) ethynyl] nicotinic acid, 6-[2-(3,5,5,8,8-pentamethyl--5,6,7,8-naphthane-2-yl) ethynyl] nicotinic acid, or they are at pharmaceutically acceptable salt.
CN88101234A 1987-03-13 1988-03-11 Acetylenes disubstituted with a heteroaromatic group and a tetralin group having retinoid like activity Expired - Fee Related CN1025612C (en)

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CN107176945B (en) * 2016-03-11 2021-06-08 中国科学院上海有机化学研究所 Retinoid compound, preparation method, intermediate and application thereof

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